Abstract:A novel and efficient method for the synthesis of difficult sequence-containing peptides has been developed based on the synthesis of O-acyl isopeptides followed by an O-N intramolecular acyl migration reaction, resulting in a remarkable improvement of the yields.
“…Depsi-peptide Aβ 1-42 was synthesized as previously described (47,48). At variance with the native peptide, the depsi-peptide is highly soluble and it has a much lower propensity to aggregate, thus preventing the spontaneous formation of seeds in the solution (49,50).…”
Inability to form new memories is an early clinical sign of Alzheimer's disease (AD). There is ample evidence that the amyloid-β (Aβ) peptide plays a key role in the pathogenesis of this disorder. Soluble, bio-derived oligomers of Aβ are proposed as the key mediators of synaptic and cognitive dysfunction, but more tractable models of Aβ−mediated cognitive impairment are needed. Here we report that, in mice, acute intracerebroventricular injections of synthetic Aβ 1-42 oligomers impaired consolidation of the long-term recognition memory, whereas mature Aβ 1-42 fibrils and freshly dissolved peptide did not. The deficit induced by oligomers was reversible and was prevented by an anti-Aβ antibody. It has been suggested that the cellular prion protein (PrP C ) mediates the impairment of synaptic plasticity induced by Aβ. We confirmed that Aβ 1-42 oligomers interact with PrP C , with nanomolar affinity. However, PrP-expressing and PrP knock-out mice were equally susceptible to this impairment. These data suggest that Aβ 1-42 oligomers are responsible for cognitive impairment in AD and that PrP C is not required.Alzheimer | neurotoxicity | object recognition test | surface plasmon resonance | protein aggregation
“…Depsi-peptide Aβ 1-42 was synthesized as previously described (47,48). At variance with the native peptide, the depsi-peptide is highly soluble and it has a much lower propensity to aggregate, thus preventing the spontaneous formation of seeds in the solution (49,50).…”
Inability to form new memories is an early clinical sign of Alzheimer's disease (AD). There is ample evidence that the amyloid-β (Aβ) peptide plays a key role in the pathogenesis of this disorder. Soluble, bio-derived oligomers of Aβ are proposed as the key mediators of synaptic and cognitive dysfunction, but more tractable models of Aβ−mediated cognitive impairment are needed. Here we report that, in mice, acute intracerebroventricular injections of synthetic Aβ 1-42 oligomers impaired consolidation of the long-term recognition memory, whereas mature Aβ 1-42 fibrils and freshly dissolved peptide did not. The deficit induced by oligomers was reversible and was prevented by an anti-Aβ antibody. It has been suggested that the cellular prion protein (PrP C ) mediates the impairment of synaptic plasticity induced by Aβ. We confirmed that Aβ 1-42 oligomers interact with PrP C , with nanomolar affinity. However, PrP-expressing and PrP knock-out mice were equally susceptible to this impairment. These data suggest that Aβ 1-42 oligomers are responsible for cognitive impairment in AD and that PrP C is not required.Alzheimer | neurotoxicity | object recognition test | surface plasmon resonance | protein aggregation
“…As we will show here, switch-elements can be composed of depsipeptide (also called O-peptide or O-acyl isopeptide) units and/or pseudoprolines (CPro). So far, acyl transfer reactions have been the subject of extensive mechanistic studies, 24 and their role in protein biosynthesis and splicing, 25,26 peptide synthesis and solubilization, [27][28][29][30] prodrug design [31][32][33][34][35][36] and native chemoselective ligation strategies [37][38][39] has found broad attention. Our focus over the last few years was directed toward the elaboration of the concept of ''switch-peptides'' for the study of peptide self-assembly, secondary structure formation, and disruption.…”
“…N acyl migration. [5][6][7][8][9][10][11][12][13][14][15][16] However, because of the special synthetic and purification skills required to prepare the full-length Ab switch-peptides, such peptides are not suitable for use in highthroughput screening assays. Therefore, the development of reliable model systems that are readily accessible and adaptable to automated HTS is of particular interest to understanding the mechanism of amyloid formation and facilitating the discovery of aggregation inhibitors of Ab and other amyloid-forming proteins.…”
Section: Introductionmentioning
confidence: 99%
“…Previously, we [5][6][7][8] and others [9][10][11][12] have shown that various steps along the amyloid formation pathway, including peptide/ protein misfolding, self-assembly, and amyloid formation and disassembly, can be triggered in a highly controllable manner through the incorporation of molecular switches into the amyloid-forming polypeptides, based on in situ intramolecular O! N acyl migration.…”
Several amyloid‐forming proteins are characterized by the presence of hydrophobic and highly amyloidogenic core sequences that play critical roles in the initiation and progression of amyloid fibril formation. Therefore targeting these sequences represents a viable strategy for identifying candidate molecules that could interfere with amyloid formation and toxicity of the parent proteins. However, the highly amyloidogenic and insoluble nature of these sequences has hampered efforts to develop high‐throughput fibrillization assays. Here we describe the design and characterization of host–guest switch peptides that can be used for in vitro mechanistic and screening studies that are aimed at discovering aggregation inhibitors that target highly amyloidogenic sequences. These model systems are based on a host–guest system where the amyloidogenic sequence (guest peptide) is flanked by two β‐sheet‐promoting (Leu‐Ser)n oligomers as host sequences. Two host–guest peptides were prepared by using the hydrophobic core of Aβ comprising residues 14–24 (HQKLVFFAEDV) as the guest peptide with switch elements inserted within (peptide 1) or at the N and C termini of the guest peptide (peptide 2). Both model peptides can be triggered to undergo rapid self‐assembly and amyloid formation in a highly controllable manner and their fibrillization kinetics is tuneable by manipulating solution conditions (for example, peptide concentration and pH). The fibrillization of both peptides reproduces many features of the full‐length Aβ peptides and can be inhibited by known inhibitors of Aβ fibril formation. Our results suggest that this approach can be extended to other amyloid proteins and should facilitate the discovery of small‐molecule aggregation inhibitors and the development of more efficacious anti‐amyloid agents to treat and/or reverse the pathogenesis of neurodegenerative and systemic amyloid diseases.
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